Researchers at the Stevens Institute of Technology have identified a mechanism that helps explain how colorectal cancer (CRC) develops, persists, and resists treatment. The research, published in the journal Cell Death & Disease, shows that mature intestinal cells that revert to a stem cell-like state can sustain tumor growth more effectively than mutated intestinal stem cells, a finding that could inform new drug development strategies focused on preventing CRC recurrence.
“Our study suggests that intestinal cancers can arise not just from damaged stem cells, but also from cells that revert into stem-like cancer cells,” said senior author Ansu Perekatt, PhD, an assistant professor of chemistry and chemical biology at Stevens Institute of Technology, “and they may contribute to why colorectal cancer can be diverse and resistant to treatment.”
Colorectal cancer is the second leading cause of cancer-related death worldwide. Cancer stem cells are known to play a role in tumor growth, metastasis, treatment resistance, and relapse. The new study focused on understanding how these cancer-driving stem cell populations emerge within the intestinal epithelium.
Two different models have been proposed for how colorectal cancer can develop. The most widely held belief is the “bottom-up” model which suggests that mutations in stem cells initiate tumor formation. By comparison, the “top-down” model suggests that mature epithelial cells acquire mutations, dedifferentiate into stem-like cells, and then drive tumor growth. Histological features observed in many human colorectal tumors have suggested a luminal, or top-down, origin.
Under normal conditions, Lgr5-positive stem cells reside in intestinal crypts and their role is to replenish the intestinal lining. As their progeny migrate from the crypts toward the villi in the intestine walls, they stop dividing and become specialized mature cells. However, previous research has shown that the intestinal epithelium is highly plastic and that differentiated cells can regain stem cell characteristics under certain conditions.
To better understand the biology of these pathways, the Stevens employed mouse model carrying Smad4 loss-of-function and β-catenin gain-of-function mutations, to mimic two common drivers of human colorectal cancer. They then tracked the behavior of both stem cells and differentiated epithelial cells.
The researchers also performed single-cell RNA sequencing to characterize the cellular populations that emerged during tumor initiation and progression allowing them to compare mutant stem cells residing in the crypts with dedifferentiation-derived stem-like cells arising in the villi.
The data showed that mutant Lgr5-positive stem cells in the crypts were at a competitive disadvantage. While they carried cancer-associated mutations, many were displaced and ultimately replaced by normal stem cells. At the same time, a subset of progenitor and epithelial cells underwent dedifferentiation and reacquired stem-cell properties making them capable of sustaining tumor growth.
“We don’t know why they change and why only a subset changes,” Perekatt said. “It’s very random, very sporadic. But when they change, they develop tumors.”
According to the study, dedifferentiating epithelial cells showed early expression of both CD44 and Lgr5, markers associated with stemness and tumor initiation. The Stevens team also found abnormal activation of Notch signaling in villus epithelial cells before the formation of tumor-associated crypt structures, suggesting that this pathway may contribute to the acquisition of stem-like properties.
The dedifferentiation-derived cells showed growth-factor independence, which allows them to proliferate without relying on the supportive niche environment normally required by stem cells. They also exhibited metabolic adaptations associated with tumor survival.
The study also found evidence of stem-cell heterogeneity within tumors. Single-cell analysis identified populations with distinct proliferative, signaling, and metabolic states. One mutant stem-cell cluster exhibited cancer-associated and embryonic stem cell-like gene signatures, while other clusters appeared more quiescent.
“Our findings suggest that metabolic adaptations and dedifferentiation-driven stem cell heterogeneity may enhance adaptability and confer a selective advantage driving top-down tumorigenesis,” the researchers wrote.
The findings have implications for current and future treatment strategies. Many therapies focus on eliminating actively growing cancer cells, but the study suggests that stem-like cells generated through dedifferentiation may remain capable of regenerating tumors after treatment. Targeting the mechanisms that enable mature epithelial cells to revert to a stem-like state could prove an effective method for preventing cancer recurrence.
“If you are only treating the cells that become cancerous without targeting the cells that acquired the de novo stemness, the cancer will likely come back,” Perekatt said. “So it’s really important to understand what causes this reversion to stemness, in order to develop new and effective therapies for colorectal cancers.”
Future research will focus on unanswered questions raised by the study, including the source of the Notch signals that trigger dedifferentiation, the transcriptional programs activated during this process, and the metabolic vulnerabilities of the resulting stem-like tumor cells.
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